JPS6249274B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to novel carboxylic acid amide derivatives. The carboxylic acid amide derivative of the present invention is a novel compound that has not been described in any literature, and is represented by the following general formula [1]. [In the formula, R ¹ represents a hydrogen atom or a halogen atom. X
represents a lower alkylene group that may have a phenyl group as a substituent.

[Formula] is −(CH ₂ ) ₄ −, −(CH ₂ ) ₅ −,

[Formula] − (CH ₂ ) ₂ O(CH ₂ ) ₂ − or

[Formula], R ² is a hydrogen atom, a lower alkyl group that may have a hydroxyl group as a substituent, a phenyl lower alkyl group, a lower alkoxycarbonyl group, or a halogen atom, a lower alkoxy group, a lower alkyl group as a substituent and a phenyl group which may have a group selected from halogen-substituted lower alkyl groups. ] The carboxylic acid amide derivative represented by the above general formula [1] has anti-inflammatory effects, analgesic effects, antipyretic effects, etc., and is useful as an anti-inflammatory agent, analgesic agent, and antipyretic agent. In the above general formula [1], R ¹ , X and

Examples of the group defined by the formula and other groups used herein include the following. Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom. Examples of lower alkylene groups that may have a phenyl group as a substituent include methylene, ethylene, propylene, isopropylene, butylene,
Pentamethylene, hexamethylene, methylmethylene, phenylmethylene, 1-phenylethylene,
2-phenylethylene, 1-phenylpropylene, 2-phenylpropylene, 3-phenylpropylene, 1-phenylbutylene, 2-phenylbutylene, 3-phenylbutylene, 4-phenylbutylene, 1 -Phenylpentamethylene, 2-phenylpentamethylene, 3-phenylpentamethylene, 4-phenylpentamethylene, 5-phenylpentamethylene, 1-phenylhexamethylene, 2-phenylhexamethylene, 3- Phenylhexamethylene, 4-phenylhexamethylene,
Examples include 5-phenylhexamethylene and 6-phenylhexamethylene groups. Examples of lower alkyl groups that may have a hydroxyl group as a substituent include methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, hexyl, hydroxymethyl,
1-hydroxyethyl, 2-hydroxyethyl,
Examples include 1-hydroxypropyl, 2-hydroxypropyl, 3-hydroxypropyl, 1-hydroxybutyl, 2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl, 5-hydroxypentyl, 6-hydroxyhexyl group, etc. can. Examples of the phenyl lower alkyl group include benzyl, α-phenethyl, β-phenethyl, 3-phenylpropyl, 4-phenylbutyl, 1.1-
Examples include dimethyl-2-phenylethyl, 5-phenylpentyl, and 6-phenylhexyl groups. Examples of lower alkoxycarbonyl groups include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl,
Examples include butoxycarbonyl and tert-butoxycarbonyl groups. Examples of lower alkoxy groups include methoxy,
Examples include ethoxy, propoxy, isopropoxy, butoxy and tert-butoxy groups. Examples of lower alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, and hexyl groups. Examples of the halogen-substituted lower alkyl group include trifluoromethyl, trichloromethyl, 2.
Examples include 2,2-trifluoroethyl group. Examples of the phenyl group that may have a substituent selected from a halogen atom, a lower alkoxy group, a lower alkyl group, and a halogen-substituted lower alkyl group include phenyl, 2-methylphenyl, 4-methylphenyl, and 3-trifluoro. Methyl, 2-ethylphenyl, 4-trichloromethylphenyl, 2-methoxyphenyl, 4-methoxyphenyl, 3-ethoxyphenyl, 4-chlorophenyl, 2-fluorophenyl, 4-fluorophenyl, 2-chlorophenyl Examples include groups. Also, in general formula [1]

Examples of the group represented by the formula include a pyrrolidino group, a piperidino group, and 4-ketopiperidino (γ-piperidonyl).
, a morpholino group and a piperazino group having a group represented by R ² . The carboxylic acid amide derivative of the present invention can be produced, for example, by the methods shown in Reaction Formulas -1 and -2 below. Reaction formula-1 [In the formula, Z represents a fluorine, chlorine, bromine or iodine atom, and R ¹ and X are as defined above.

[Formula] is −(CH ₂ ) ₄ −, −(CH ₂ ) ₅ −,

[Formula] −(CH ₂ ) ₂ O(CH ₂ ) ₂ − or

[Formula] is shown, and R ² ' represents the above R ² group other than a hydrogen atom. ] That is, among the carboxylic acid amide derivatives of the present invention, the compound represented by the general formula [1-a] is a thiazolo[5,4-b]pyridin-2(1H)-one derivative (compound of the general formula [2]) and a haloamide. It can be obtained by reacting with a derivative (compound of general formula [3]). The above reaction is carried out in the presence of a deoxidizing agent. As the deoxidizing agent, any conventionally known basic compound can be used, and specifically, organic bases such as pyridine, triethylamine, diethylaniline, N-methylmorpholine, and triethylenediamine, sodium carbonate, potassium carbonate, lithium hydroxide,
Examples include inorganic bases such as sodium hydroxide, potassium hydroxide, sodium hydride, sodium methoxide, potassium methoxide, sodium ethoxide, and potassium ethoxide. Among these, it is particularly advantageous to use inorganic bases as deoxidizing agents. Also, the compound of the above general formula [2] and the general formula [3]
The reaction with the compound is generally carried out in a suitable solvent. Any solvent can be used as long as it does not adversely affect the reaction. Specifically, aromatic or aliphatic hydrocarbons such as benzene, toluene, xylene, and petroleum ether; chain or cyclic ethers such as ethyl ether, methyl phenyl ether, tetrahydrofuran, and dioxane; and acetone, methyl ethyl ketone, acetophenone, etc. Ketones; lower alcohols such as methanol, ethanol, isopropanol, etc. are appropriately selected and used depending on the type of deoxidizing agent used, the properties of the raw materials, and other reaction conditions. In this reaction, the ratio of the compound of general formula [2] and the compound of general formula [3] to be used is not particularly limited and can be appropriately selected from a wide range, but usually the latter is used in equimolar to excess amounts relative to the former. Preferably, it is used in an equimolar amount. Further, it is preferable to use the deoxidizing agent in an amount of about 1 to 2 times the mole of the compound of general formula [2]. The reaction may be carried out under cooling, at room temperature, or under heating, but is usually preferably carried out at room temperature to the reflux temperature of the solvent. The reaction is generally completed in about 3 to 20 hours. Reaction formula-2 [In the formula, R ¹ , X and R ² ' are the same as above. ] Among the carboxylic acid amide derivatives of the present invention, the compound represented by the general formula [1-b] is a compound represented by the above reaction formula -
As shown in 2, it is produced by acid decomposition of a compound represented by the general formula [1-a']. The compound represented by the general formula [1-a'] can be obtained by the method shown in the above reaction formula-1, and among them, especially
Compounds in which R ² ' is a lower alkoxycarbonyl group are preferably used in this reaction. The acid used in this reaction is preferably hydrogen halide, especially 20-30% of hydrogen bromide.
Acetic acid solution is good. The usage ratio is determined by the general formula [1-
a′] is preferably 30 to 40 times the weight of the compound. This reaction can be carried out either under cooling or at room temperature, but it is usually better to carry out it at room temperature. This reaction generally requires a long time and is preferably carried out for 3 to 4 days. The compound of the present invention thus obtained can be easily isolated and purified by conventional separation means such as solvent extraction, recrystallization, column chromatography, preparative thin layer chromatography, and the like. Further, the compound of the present invention can be easily formed into a salt by reacting with a pharmaceutically acceptable acidic compound. The present invention also includes salts of the compound of general formula [1]. In order to explain the present invention in more detail, production examples of the compounds of the present invention will be given below as examples. Example 1 Thiazolo[5,4-b]pyridine-2(1H)-
Suspend 0.30 g of sodium hydride in 20 ml of dry tetrahydrofuran, add sodium hydride (50
%, oily) add 0.15g little by little. After stirring for 20 minutes under ice-cooling, a solution of 0.54 g of 1-chloroacetyl-4-(4-methoxyphenyl)piperazine in 10 ml of dry tetrahydrofuran was added dropwise, and the mixture was heated under reflux for 6 hours. After cooling, 30 ml of water is added to the reaction mixture and extracted with chloroform. After drying over Glauber's salt, the solvent is distilled off. The crystal residue was recrystallized from benzene-n-hexane to give 1-{(1,2-dihydro-2-oxothiazolo[5,4-b]pyridin-1-yl)
0.44 g of colorless needle-like crystals of acetyl}-4-(4-methoxyphenyl)piperazine were obtained. mp187.0−188.5
°C (decomposition). Example 2 1-{(1,2-dihydro-
2-oxothiazolo[5,4-b]pyridine-1
-yl)acetyl}-4-ethoxycarbonylpiperazine (1.05 g) was added, and the mixture was stirred for 3 days. 30 ml of ice-cooled, stirred water and then 4N aqueous sodium hydroxide solution are added to the reaction mixture to make the reaction mixture alkaline. Extract with chloroform and dry over Glauber's salt. After evaporating the solvent, the residue was subjected to silica gel column chromatography (eluted with chloroform/methanol (2:1)) to obtain (1,2-dihydro-
2-oxothiazolo[5,4-b]pyridine-1
-yl)acetylpiperazine was obtained. Recrystallization from benzene gave 0.33 g of colorless crystals. mp156−157℃ (decomposition). Examples 3 to 14 Each compound listed in Table 1 below was obtained in the same manner as in Example 1 above. Table 1 also lists the compounds obtained in Examples 1 and 2 above.

【table】

【table】

[Table] The test was conducted on the compound obtained in Example 4 ^* . ^1H
−NMR (CDCl ₃ , internal standard TMS) analysis results are as follows:
It was as follows. Example 4 δppm=1.3~1.8 (m, 6H) 1.8~2.3 (m, 2H) 2.42 (t, 2H) 3.2~3.7 (m, 4H) 4.03 (t, 2H) 7.2 (dd, 1H) 7.65 (dd , 1H) 8.26 (dd, 1H)

Claims (1)

[Claims] 1. General formula [In the formula, R ¹ represents a hydrogen atom or a halogen atom. X
represents a lower alkylene group that may have a phenyl group as a substituent. [Formula] represents -(CH ₂ ) ₄ -, -(CH ₂ ) ₅ -, [Formula] - (CH ₂ ) ₂ O(CH ₂ ) ₂ - or [Formula], R ² is a hydrogen atom, substitution A lower alkyl group, a phenyl lower alkyl group, a lower alkoxycarbonyl group that may have a hydroxyl group as a group, or a group selected from a halogen atom, a lower alkoxy group, a lower alkyl group, and a halogen-substituted lower alkyl group as a substituent. phenyl group. ] A carboxylic acid amide derivative represented by